Photodynamic therapy (PDT) is an emerging treatment modality that has shown promise for many types of disease, including cancer. However, selective delivery of photosensitizers (PS) to tumors remains a problem. In the clinic, PS delivery is achieved through a passive approach, by controlling the time that interval between the PS injection and light irradiation (Lovell J. F., et al., Chem Rev. 2010; 110:2839-2857). This lack of a targeting mechanism causes poor tumor selectivity, leading to a tumor/normal tissue accumulation ratio that is typically less than 2 (Orenstein A., et al., Br J Cancer. 1996; 73:937-944). As a result, PDT is often associated with off-target damage to the normal organs (e.g., the skin) and surrounding tissues. Patients undergoing PDT are required to stay away from sunlight, or even room light to avoid phototoxicity, a side effect that can last for 1-2 months (Dougherty T. J., et al., Cancer Res. 1978; 38:2628-2635).
Efforts have been made to improve the tumor selectivity of PSs, for instance, by coupling them with a tumor-targeting ligand such as an antibody (Renno R. Z., et al., Arch Ophthalmol. 2004; 122:1002-1011; Sharman W. M., et al., Adv Drug Delivery Rev. 2004; 56:53-76). However, issues such as low loading capacity, reduced phototoxicity, and heterogeneous expression of antigens throughout the tumor mass were found, and clinical translation of these technologies has not been seen. Alternatively, a PS can be loaded, via hydrophobic-hydrophobic interactions, into polymer- or liposome-based nanoparticles (Konan Y. N., et al., J Photochem Photobiol B. 2002; 66:89-106; Bechet D., et al., Trends Biotechnol. 2008; 26:612-621). This approach, however, is usually associated with a relatively low loading rate (less than 10 wt %) and a large particle size (around or larger than 100 nm), both factors can be detrimental to the PS delivery (Bechet D., et al. and Chatterjee D. K., et al., Adv Drug Delivery Rev. 2008; 60:1627-1637). There is a need for photosensitizers that have high tumor selectivity. There is also a need for photosensitizer carriers that have a high loading capacity.
Photosensitizers, while not toxic individually, can be activated by light of a specific wavelength. This causes energy transfer to near-by oxygen molecules that produces cytotoxic 1O2. A common target in conventional PDT is the tumor vasculature (Nishiyama, N., Adv. Drug Deliv. Rev. 2009; 61: 327-338). In the clinic, vasculature PDT is achieved by controlling the time interval between photosensitizer injection and illumination, the so called “drug-light interval.” Lacking selectivity, this toxicity acts on both endothelial and luminal targets (e.g. red blood cells/platelets), causing massive destruction that include vessel collapse and thrombus formation (Dolmans, D. E., et al., Nat. Rev. Cancer 2003; 3: 380-387). There is a need for photosensitizers for selective delivery that can be managed to increase vessel permeability but not induce occlusion. Particles injected subsequently can benefit from the permeabilized endothelium for enhanced accumulation in tumors. For example, unlike conventional small-molecule chemotherapeutics, nanoparticle- or macromolecule-based drugs can selectively egress at leaky tumor vasculatures and remain in the tumor interstitium for an extended period of time. However, despite relative leakiness compared to normal vessels, the endothelial lining can remain a barrier to the delivery of nanoparticles to tumors. This hindrance varies among tumors of different origins, stages, and organs, and may affect the treatment efficacy significantly. Prior work in this respect has focused on chemical-based vascular mediators such as nitroglycerin, ACE inhibitor, and PGE1 agonist (Maeda, H., et al., Adv. Drug Deliv. Rev. 2013; 65: 71-79). With these, a 2˜3 fold increase of EPR effect in tumors can be achieved. This approach, however, may potentially cause side effects to normal vasculatures and organs due to the systematic nature.
What are needed are compositions comprising a photosensitizer and that can target cancer cells. Methods for treating cancer and methods for increasing the permeability of the tumor vasculature system are also needed. Further, methods for improving the efficacy of anti-tumor drugs in a subject are needed. The compositions and methods disclosed herein address these and other needs.